S1618 tisagenlecleucel appears effective and safe in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia with high-risk cytogenetic abnormalities

Background: Cytogenetic and molecular genetic findings at diagnosis constitute important independent prognostic and risk stratification factors in B‐cell acute lymphoblastic leukemia (ALL). Certain alterations signify high‐risk (HR) cytogenetic abnormalities and are associated with poorer prognosis and inferior outcomes, particularly in patients (pts) with relapsed/refractory (r/r) disease. Tisagenlecleucel is an anti‐CD19 chimeric antigen receptor (CAR)‐T cell therapy approved in multiple countries/regions for the treatment of pediatric and young adult pts with r/r ALL (r/r pALL). Tisagenlecleucel has demonstrated high rates of durable responses and a manageable safety profile in the ELIANA and ENSIGN trials. Aims: We analyzed outcomes in a subgroup of pts from the ELIANA and ENSIGN studies with reported HR cytogenetic abnormalities at enrollment, namely: hypodiploidy; t(9;22)(q34;q11.2)/ BCR‐ABL1 ; KMT2A (MLL) rearrangement; intrachromosomal amplification of chromosome 21 (iAMP21); t(17;19)(q23;p13), encoding TCF3‐HLF fusion; BCR‐ABL1‐like; CRLF2 rearrangement; and/or TP53 mutation/deletion. Methods: ELIANA and ENSIGN are single‐arm, multicenter, phase 2 trials of tisagenlecleucel in pts with r/r pALL. The primary endpoint is overall remission rate (ORR: complete remission [CR] + CR with incomplete blood count recovery [CRi]) within 3 months per independent review committee (IRC) assessment. In this subgroup analysis, pooled efficacy and safety data from ELIANA and ENSIGN are presented for pts with HR cytogenetic abnormalities. Results: A total of 29/137 infused pts (ELIANA 13/79, ENSIGN 16/58) were identified with HR cytogenetic abnormalities (Table). Median age was 12 years (range, 3–21 years); median previous lines of therapy was 3 (range, 1–8); and 15/29 pts received at least 1 prior hematopoietic stem cell transplant. Among all infused pts (full analysis set), 19/29 (65.5%) pts with HR cytogenetic abnormalities (vs 81/108 [75.0%] pts without the aforementioned HR cytogenetic abnormalities) from this pooled data set achieved confirmed remission per IRC assessment, and 18/19 of these responding pts were negative for minimal residual disease by flow cytometry. Of the remaining 10 pts, 4 did not reach Day 28 assessment at data cutoff, 3 died before Day 28 assessment (1 each from progressive leukemia, cerebral hemorrhage, and embolic stroke), 2 had missing assessments, and 1 did not respond to therapy. Among the 19 responding pts, 4 relapsed; the median duration of response was not reached, with estimated relapse‐free probability at 12 and 24 months after remission onset of 74.6% (vs 61.7% and 58.5%, respectively, in pts without HR cytogenetic abnormalities). Median overall survival in pts with HR cytogenetic abnormalities was not reached, with estimated 12‐ and 24‐month survival probability of 74.9% and 66.6%, respectively (vs 70.7% and 58.8%, respectively, in pts without HR cytogenetic abnormalities). Rates of select adverse events that occurred within 8 weeks after infusion in pts with HR cytogenetic abnormalities were: cytokine release syndrome (grade 3, 17.2%; grade 4, 27.6%), infections (grade 3, 13.8%; grade 4, 3.4%), cytopenias not resolved by Day 28 (grade 3, 17.2%; grade 4; 13.8%), and neurological events (grade 3, 3.4%; no grade 4 events). Summary/Conclusion: In pts with HR cytogenetic abnormalities with historically poor prognosis, tisagenlecleucel appears effective, with high rates of durable responses, prolonged survival, and a manageable safety profile. image Clinical trial information: NCT02435849; NCT02228096.